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Category: genetics

‘Mob breaker’ TRIM37 prevents abnormal cell division by eliminating extra spindle poles

In 2000, researchers discovered that mutations that inactivate a gene known as TRIM37 cause a developmental disease called Mulibrey nanism. The extremely rare inherited disorder leads to growth delays and abnormalities in several organs, causing afflictions of the heart, muscles, liver, brain and eyes. In addition, Mulibrey nanism patients exhibit high rates of cancer and are infertile.

In 2016, UC San Diego School of Biological Sciences researchers in the labs of Professors Karen Oegema and Arshad Desai began understanding how TRIM37, when operating normally, plays a key role in preventing conditions that lead to Mulibrey nanism. They linked TRIM37 to spindles, which separate chromosomes during , and centrosomes, the spherical organizing structures at each end of spindles.

The image above shows a normal mitotic cell (left) compared to a cell lacking TRIM37 (right), with spindle microtubules (green), centrosomal protein centrobin (magenta) and DNA (white). Normal cells have two spindle poles that ensure proper cell division. Cells lacking TRIM37 frequently have extra spindle poles, containing a cluster of centrobin molecules that disrupt proper cell division. Patients with Mulibrey nanism lack TRIM37 and their cells show similar extra spindle poles.

Genome-wide association study of proteomic aging reveals shared genetic architectures with longevity, early life development, and age-related diseases

There is still relatively little known about the genetic underpinnings of proteomic aging clocks. Here, we describe a genome-wide association study of proteomic aging in the UK Biobank (n=38,865), identifying 27 loci associated with participants’ proteomic age gap (ProtAgeGap). ProtAgeGap exhibits a strong genetic correlation with longevity (rg = −0.83), and in FinnGen a ProtAgeGap polygenic score (PGS) was associated with significantly increased odds of achieving longevity (n=500,348; OR = 1.43). Additional PGS analyses in All of Us (n=117,415), China Kadoorie Biobank (n=100,640), and ABCD Study (n=5,204) demonstrate reproducible associations across biobanks of ProtAgeGap PGS with obesity, cardiometabolic disease, and osteoarthritis in adults, and with developmental timing in children. Finally, colocalization analysis identified FTO as an obesity-related mechanism uniting diverse aging traits. Our results demonstrate a shared genetic architecture across the life course of ProtAgeGap with longevity, early developmental biology, and cardiometabolic and musculoskeletal diseases.

### Competing Interest Statement.

The authors have declared no competing interest.

Rejuvenating aged haematopoietic stem cells by targeting RhoA

In their nucleus, as they replicate, blood stem cells can accumulate mutations and lose epigenetic marks that used to keep DNA well-arranged, ultimately increasing mechanical tension on the nuclear envelope. This study figured out RhoA is a mechanosensor activated by such tension and conducts a key role in the stem cell ageing process. Researchers subsequently proved its rejuvenating potential: after ex vivo treatment of blood stem cells with the drug Rhosin, a RhoA inhibitor, they observed an improvement in aged-related markers.

As study co-author summarizes: “Overall, our experiments show that Rhosin did rejuvenate blood stem cells, increased the regenerative capacity of the immune system and improved the production of blood cells once transplanted in the bone marrow.”

Ageing is defined as the deterioration of function overtime, and it is one of the main risk factors for numerous chronic diseases. Although ageing is a complex phenomenon affecting the whole organism, it is proved that the solely manifestation of ageing in the haematopoietic system affects the whole organism.

A research team previously revealed the significancy of using blood stem cells to pharmacologically target ageing of the whole body, thereby suggesting rejuvenating strategies that could extend healthspan and lifespan. Now, in a Nature Ageing publication, they propose rejuvenating aged blood stem cells by treating them with the drug Rhosin, a small molecule that inhibits RhoA, a protein that is highly activated in aged haematopoietic stem cells. This study combined in vivo and in vitro assays together with innovative machine learning techniques.

Blood stem cells, or hematopoietic stem cells, are located in the bone marrow, a highly dynamic and specialised tissue within the cavity of long bones. They are responsible for the vital function of continuously producing all types of blood cells: red blood cells (oxygen transporters), megakaryocytes (future platelets) and white blood cells (immune cells, lymphocytes and macrophages). Over time, however, stem cells also do age, they lose their regenerative capacity and generate fewer and lower quality immune cells. This has been linked to immunosenescence, chronic low grade inflammation and certain chronic diseases.

Is bioluminescence the key to safe, effective brain imaging?

A decade ago, a group of scientists had the literally brilliant idea to use bioluminescent light to visualize brain activity.

“We started thinking: ‘What if we could light up the brain from the inside?’” said Christopher Moore, a professor of brain science at Brown University. “Shining light on the brain is used to measure activity — usually through a process called fluorescence — or to drive activity in cells to test what role they play. But shooting lasers at the brain has down sides when it comes to experiments, often requiring fancy hardware and a lower rate of success. We figured we could use bioluminescence instead.”

With a major grant from the National Science Foundation, the Bioluminescence Hub at Brown’s Carney Institute for Brain Science launched in 2017 based on collaborations between Moore (associate director of the Carney Institute), Diane Lipscombe (the institute’s director), Ute Hochgeschwender (at Central Michigan University) and Nathan Shaner (at the University of California San Diego).

The scientists’ goal was to develop and disseminate neuroscience tools based on giving nervous system cells the ability to make and respond to light.

In a study published in Nature Methods, the team described a bioluminescence tool it recently developed. Called the Ca2+ BioLuminescence Activity Monitor — or “CaBLAM,” for short — the tool captures single-cell and subcellular activity at high speeds and works well in mice and zebrafish, allowing multi-hour recordings and removing the need for external light.

More said that Shaner, an associate professor in neuroscience and in pharmacology at U.C. San Diego, led the development of the molecular device that became CaBLAM: “CaBLAM is a really amazing molecule that Nathan created,” Moore said. “It lives up to its name.”

Measuring ongoing activity of living brain cells is essential to understanding the functions of biological organisms, Moore said. The most common current approach uses imaging with fluorescence-based genetically encoded calcium-ion indicators.

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Reversing aging in blood stem cells by targeting lysosomal dysfunction

As people age, these cells become defective and lose their ability to renew and repair the blood system, decreasing the body’s ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.

The team discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells’ metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function.

The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out “inflammation” signals that can cause damage in the body.

Remarkably, ex vivo treatment (when cells are removed from the body, modified in a laboratory, and returned to the body) of old stem cells with the lysosomal inhibitor boosted their in vivo blood-forming capacity more than eightfold, demonstrating that correcting lysosomal dysfunction can restore regenerative potential.

This restoration also dampened harmful inflammatory and interferon-driven pathways by improving lysosomal processing of mitochondrial DNA and reducing activation of the cGAS-STING immune signaling pathway, which they find to be a key driver of inflammation and aging of stem cells.

Researchers have discovered how to reverse aging in blood-forming stem cells in mice by correcting defects in the stem cell’s lysosomes. The breakthrough, published in Cell Stem Cell, identifies lysosomal hyperactivation and dysfunction as key drivers of stem cell aging and shows that restoring lysosomal slow degradation can revitalize aged stem cells and enhance their regenerative capacity.

Continue reading “Reversing aging in blood stem cells by targeting lysosomal dysfunction” | >

Video NeuroImage: Stereotypic Motor Behaviors in a Patient With Pantothenate Kinase–Associated Neurodegeneration

A 24-year-old woman with pantothenate kinase–associated neurodegeneration (PKAN) presented with a 5-year history of psychiatric symptoms followed by prominent stereotypic motor behaviors, including repetitive touching of her mouth and leg, object manipulation, and tip-toe walking (Video 1). Examination revealed severe depression and anxiety, mild speech dysfluency, and the stereotypic movements. Previous symptomatic treatments provided limited benefit. Brain magnetic resonance imaging demonstrated the pathognomonic “eye-of-the-tiger” sign, indicative of iron deposition in the bilateral globus pallidus (Figure). Genetic testing identified compound heterozygous variants in the PANK2 gene: a known pathogenic variant (c.401AG) and a novel likely pathogenic variant (c.1465CG).

ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial

Liafensine was efficacious and well tolerated in ANK3-positive patients with treatment-resistant depression, with clinically meaningful and statistically significant improvements over placebo, highlighting ANK3 as a predictive genetic biomarker for liafensine.

Question Does the newly discovered ANK3 pharmacogenomic biomarker predict the response of patients with treatment-resistant depression (TRD) to liafensine, a triple reuptake inhibitor, despite failure in a non–biomarker-selected TRD patient population in prior phase 2b trials?

Findings In this randomized clinical trial including 189 ANK3-positive patients with TRD, liafensine demonstrated a 4.4-point Montgomery-Åsberg Depression Rating Scale improvement over placebo, a clinically meaningful and statistically significant difference.

Meaning This represents a first successful genetic biomarker-guided clinical trial in psychiatry, advancing a new treatment for TRD and providing a new path for developing precision medicines in the field.

Novel Gene Therapy Treats T Cell Leukemia

Scientists at the University College London (UCL) have developed a novel therapy that helps treat patients with T cell acute lymphoblastic leukemia (T-ALL). This form of therapy used genome editing tools to modify immune cells and boost immune system response. T-ALL is a rare and aggressive blood cancer that affects specialized immune cells, known as T cells. This immune subset is responsible for identifying and targeting foreign pathogens. Unfortunately, in T-ALL, genetic mutations prevent T cells from maturing and properly functioning.

The world’s first gene therapy (BE-CAR7) uses base-editing, which can specifically change a single base in a cell’s DNA. BE-CAR7 was the first therapy to treat T-ALL in both children and adults. In 2022, a 13-year old girl was given BE-CAR7 followed by another eight children and two adults undergoing the same treatment. The following results from these patients were published in the New England Journal of Medicine (NEJM), by Dr. Waseem Qasim and others. Qasim is a Professor of Cell and Gene Therapy in the Department of Infection, Immunity, and Inflammation at the UCL. His work focuses on pediatric oncology with a focus in gene therapy. Qasim’s work has long involved treatment of T-ALL and improving therapies for children with leukemia.

Qasim and his team reported that 82% of patients receiving BE-CAR7 achieved remission, which allowed them to undergo stem cell transplant without disease. Treatment was accompanied by tolerable side effects, including low blood counts, cytokine release syndrome, and rashes. Additionally, 64% of patients remained disease-free even after three years. These remarkable results indicate the strong impact gene therapy has on T-ALL.

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